Process for the preparation of pyrimidine derivatives

ABSTRACT

A process for the preparation of 5-substituted 4-amino-2-methylpyrimidines of the formula 
                         
wherein R is CONH 2  or CN, and of acid addition salts thereof, characterized in that a compound of formula H 2 N—CH═C(R) CN (II) is reacted with acetimidic acid methyl ester or an acid addition salt thereof and that, if desired, a compound of formula I is transferred into an acid addition salt, and the transformation of a compound of formula II wherein R is CONH 2  into a compound of formula II wherein R is CN by treatment with POCl 3 .

This application is a continuation of commonly owned copending U.S. Ser.No. 13/263,142, filed Dec. 23, 2011 (U.S. Pat. No. 8,461,168), which isthe national phase application of international applicationPCT/EP2010/054629, filed Apr. 8, 2010 which designated the U.S. andclaims benefit of EP 09157590.2, dated Apr. 8, 2009, the entire contentsof each of which are hereby incorporated by reference.

The present invention relates to the preparation of pyrimidinederivatives. More precisely, the present invention relates to thepreparation of 5-substituted 4-amino-2-methylpyrimidines of the formula

-   -   wherein R is CONH₂ or CN,        and of their acid addition salts.

The compounds of formula I and their acid addition salts are knowncompounds and intermediates in processes for the preparation of vitaminB₁ (thiamin) comprising a thiazole and a pyrimidine. One generalapproach for the synthesis of thiamine is the separate synthesis of thethiazole and the pyrimidine building blocks followed by theircondensation reaction. This method was originally reported by Williams,R. R., et al. (J. Am. Chem. Soc. 58, 1504 [1936]). An alternativegeneral method builds the thiazole ring on a preformed pyrimidineintermediate. Currently all industrial production processes use thisapproach which proceeds via the key intermediate4-amino-5-aminomethyl-2-methylpyrimidine (also called Grewe diamine).The aminomethyl side chain is extended by3-chloro-5-hydroxypentane-2-one, 3-mercaptoketone or their correspondingacetates and cyclized to the thiazole ring.

In this approach in the majority of cases malononitrile is used asstarting material for the construction of the pyrimidine ring.Malononitrile again can be obtained by addition of ammonia toacrylonitrile and subjecting the β-aminopropionitrile to oxidativedehydrogenation in the gas phase at high temperature and in the presenceof molecular oxygen and a metallic catalyst (Ullmann's Encyclopedia ofIndustrial Chemistry, 5^(th) ed., Vol. 27A, 515-517).

Since malononitril is a very cost intensive starting material for theindustrial synthesis of vitamin B₁ it was an objective to find moreappropriate substitutes for it. This problem has been solved by using acompound of formula H₂H—CH═C(R)—CN (II) wherein R is CONH₂ or CN in acyclisation with acetimidic acid methylester of formula H₃C—C(═NH)—OCH₃(III) to form the 4-amino-2-methylpyrimidine ring of vitamin B₁.

The present invention, therefore, relates to a process for thepreparation of 5-substituted 4-amino-2-methylpyrimidines of the formula

-   -   wherein R is CONH₂ or CN,        and of acid addition salts thereof, characterized in that a        compound of formula H₂N—CH═C(R)—CN (II) is reacted with        acetimidic acid methyl ester (H₃C—C(═NH)—O—CH₃) or an acid        addition salt thereof and that, if desired, a compound of        formula I is transferred into an acid addition salt.

The reaction can be carried out without a solvent or in solution. It isconveniently conducted in an inert, polar solvent, such as an aliphaticalcohol, preferably with 1-8 C-atoms, more preferably with 1-4 C-atoms,at a temperature in the range of −10 to 100° C., preferably 0-60° C. andunder a pressure of 1-10 bar, preferably 1-5 bar, if desired under aninert gas. Normally the reaction is complete after 12 hours up to 24hours.

Acid addition salts of compounds of formula (I) with organic or,norganic acids are obtained if the reaction is carried out undercorresponding acidic conditions or if a corresponding acid is addedafter the reaction. Preferred acid addition salts are the salts withhydrohalide acids; most preferred is the hydrochloride.

The 3-amino-2-cyanoacrylamid starting material is a known material andcan be obtained from formamidine and cyanoacetimide as described, e.g.,in U.S. Pat. No. 3,487,083.

Acetimidic acid methyl ester is also a known compound which iscommercially available and can be prepared, e.g., as described in EP 1840 118 A1.

The transformation of 4-amino-2-methyl-5-pyrimidinecarboxamide into4-amino-2-methyl-5-pyrimidinecarbonitril with POCl₃ by intramoleculardehydration is known, e.g., from J. Chem. Soc. 1937, 364 (Todd et. al.),although with yields only up to 50%. Own experiments to increase theyield in this reaction by variation of the reaction conditions failed.On the other hand intramolecular dehydration of3-amino-2-cyanoacrylamide with POCl₃ to 2-aminomethylene-malononitrilehas so far not been described in the literature and was achieved with ayield of 79.4% and a purity of 42.6% which result is surprising,particularly since with COCl₂ no dehydration was achieved.

Therefore, this reaction is also part of the invention.

The dehydration reaction is conveniently carried out in solution,preferably in a polar solvent, such as dimethyl formamide, dimethylacetamide or dimethoxy-ethane, at a temperature in the range of from−10° C. to 100° C., preferably from 0-60° C., under a pressure in therange of 1-10 bar, preferably 1-5 bar and preferably in the presence ofa base, e.g., an aromatic or aliphatic amine, such as pyridine or NR₃(wherein R₃ is C₁₋₄-alkyl), most preferably triethylamine. Normally thereaction is complete after 12 hours up to 24 hours.

It is interesting to note that while the cyclization of2-aminomethylene-malononitril to 4-amino-2-methyl-5-cyanopyrimidine withacetimidic acid methyl ester under the reaction conditions of thepresent invention is achieved with a yield of 60% and a puritiy of 64.8%no cyclization is achieved with acetimidine, demonstrating thatacetimidine and acetimidic acid methyl ester cannot be regarded as beingequivalent in the cyclisation of compounds II to compounds I.

The following examples illustrate the present invention in more detail.

EXAMPLE 1

1.85 g of acetamidic acid methyl ester hydrochloride (95.0%, 16.07 mmol)and 2.0 g of 3-amino-2-cyano-acrylamide (68.7%, 12.36 mmol) weresuspended in 20 ml of methanol. 2.89 g NaOMe (30%, 16.07 mmol) wereadded and the suspension was heated to 45° C. under stirring for 24hours. No conversion was observed. The reaction mixture was then heatedto 70° C. under stirring for 3.5 hours. After addition of 1.15 ml ofNaOMe methanol (30%) heating to 70° C. under stirring was continued for3 hours. The reaction mixture was filtered and the filter cake was driedunder 30 mbar/50° C. The yield of4-amino-2-methyl-5-pyrimidinecarboxamide was 2.25 g (purity 30.1%). Themother liquor was concentrated under 30 mbar/50° C. and yielded afurther 1.0 g of the product (purity 12.3%). Total yield: 42.5%.

EXAMPLE 2

To a mixture of 0.60 g of 3 amino-2-cyano-acrylamide (82.2%, 4.44 mmol)and 20 ml of dimethoxyethane 0.56 g of triethylamine (99.5%, 5.52 mmol)was added at room temperature. Then 0.56 g of POCl₃ (98.0%, 3.55 mmol)was added dropwise. The suspension turned yellow and after 5 hours allvolatiles were removed under 30 mbar/42° C. 780 mg of2-aminomethylene-malononitrile were obtained.

Yield: 79.4%; purity 42.6%. A higher purity can be reached by extractionof the product in aqueous NaOH (28%) with dichloromethane.

EXAMPLE 3

27.97 g of NaOMe in methanol (13.72 mmol, 2.7%) were added to 1.58 g ofacetimidic acid methylester hydrochloride (95.0%, 13.72 mmol) and 1.43 gof 2-aminomethylene-malononitrile (68.7%, 10.55 mmol) and the mixturewas stirred for 5 hours at room temperature under argon. While the4-amino-2-methyl-5-pyrimidinecarbonitril did not precipitate even withaddition of sodium chloride and cooling to 0° C. work-up was achieved byremoving all volatiles under 30 mbar/48° C. The remaining solids weresuspended in water and filtered. The filter cake was dried and analyzedby NMR. Yield of pyrimidinecarbonitril: 1.33 g (60.0%, purity 64.8%).

EXAMPLE 4

To a mixture of 0.68 g of 3-amino-2-cyanoacrylamide (82.2%, 5.03 mmol)and 10 ml of dimethoxyethane 0.63 g of triethylamine (99.5%, 6.26 mmol)were added. Then 0.63 g of POCl₃ (98.0%, 4.02 mmol) were added dropwiseupon which the suspension turned brownish. After two hours of stirringat room temperature there were still 20% of starting material left.Additional POCl₃ (0.17 ml) was added dropwise. After three hours allvolatiles were removed at 30 mbar, 40° C. The remaining solid residuewas dissolved in 10 ml of methanol and 0.75 g of acetimidic acidmethylester hydrochloride (95.0%, 6.54 mmol) was added. Then 13.33 g ofNaOMe in methanol (2.7%, 6.54 mmol) were added and the mixture wasstirred for 18 hours at 45° C. Only 2-aminomethylene-malononitrile wasfound, no pyrimidinecarbonitrile.

EXAMPLE 5

To a mixture of 0.41 g of 2-aminomethylene-malononitrile (4.44 mmol) in10 ml of isopropanol a solution of 2.74 g of acetamidine in isopropanol(9.9%, 4.66 mmol) was slowly added. After stirring the suspension forfour hours at room temperature no pyrimidinecarbonitril was detected inthe reaction mixture.

The invention claimed is:
 1. A process for the preparation of5-substituted 4-amino-2-methylpyrimidine of the formula

wherein R is CONH₂, and acid addition salts thereof, wherein the processcomprises reacting a compound of formula H₂N—CH═C(R)—CN (II) withacetimidic acid methyl ester or an acid addition salt thereof or,optionally, transferring a compound of formula I into an acid additionsalt.